Pharmacogenetics involves the study of host susceptibility and environmental exposure in cancer development. The unique contribution of this discipline is that the genes studied are common, the role of the environment more explicit because the mechanism of the polymorphic enzymes of interest is know, and the study base is the population rather than the family. A broad range of studies of pharmacogenetic variability and the relationship to carcinogenesis are underway. We have developed methodologies to perform phenotyping with various probe drugs (debrisoquine, caffeine, and dextromethorphan). The relationship of phenotype to genotype has been explored, with major contributions in understanding how various CYP2D6 mutations impact on the phenotype, including the discovery of a new mutation. We recognized and documented ethnic and racial variation in putative genetic susceptibility factors and we have described its implications. Cancer associations have been studied: with regard to lung cancer, heterogeneity was observed with regard to CYP2D6, and no association observed for p53, l-myc, CYP1A1, and CYP2E1 polymorphisms. We have reported one of the first examples of exposure-susceptibility gene effects relevant to cancer with descriptions of the relationship of the acetylation phenotype to 4-aminobiphenyl hemoglobin (ABP) adducts and tobacco type and quantity. Studies of important exposures such as dioxin and nicotine that may exhibit pharmacogenetic variation have been initiated. New pharmacogenetic hypotheses have been generated for other cancers: nasopharyngeal carcinoma, colon, breast, prostate, and head and neck. Case-case studies of lung and bladder cancer have been initiated or planned to better understand the role of cofactors in there association.